Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by resting tremor, rigidity and bradykinesia. These clinical features are thought to arise from reduced dopaminergic input to the striatum, which is caused by the degeneration of dopaminergic neurons in the substantia nigra. The occurrence of PD is largely sporadic, but clinical syndromes resembling sporadic PD can also be caused by mutations in the asynuclein, parkin, DJ-1 and PINK1 genes. Elucidation of the pathogenic mechanisms underlying the selective dopaminergic degeneration in familial parkinsonism will likely provide important clues to the pathogenic mechanisms responsible for idiopathic PD. The recent identification of the parkinsonian genes made it possible to investigate the underlying pathogenic mechanism by employing genetic approaches. The central hypothesis underlying our research is that the familial parkinsonism-linked mutations alter the normal physiology of dopaminergic neurons in the substantia nigra, ultimately leading to the degeneration of dopaminergic neurons and the production of motor impairments. Our previous generation and analysis of parkin-/- mice have shown nigrostriatal deficits and mitochondrial dysfunction in the absence of loss of dopaminergic neurons, suggesting that these dopaminergic functional deficits likely precede neurodegeneration, and that mitochondrial dysfunction may be causal in PD pathogenesis. In this proposal, we hypothesize that loss-of-function mutations in the DJ-1 gene alter the normal physiology of dopaminergic neurons, and that the presence of multiple pathogenic mutations accelerates dopaminergic dysfunction and degeneration, leading to progressive loss of dopaminergic neurons in mice. To test these hypotheses, we propose the following Specific Aims. First, we will generate and analyze DJ-1-null mice for disruption of normal dopaminergic neurotransmission, loss of dopaminergic neurons and motor impairments. Second, we will determine whether loss of DJ-1 function results in mitochondrial dysfunction and increased oxidative damage. Third, since mouse models bearing mutations in a single pathogenic gene, such as parkin-null and alpha-synuclein transgenic mice, fail to develop the cardinal future of PD, namely selective dopaminergic degeneration, we will investigate whether the presence of multiple pathogenic mutations (alpha-synuclein Tg; parkin-/-; DJ-1-/-) accelerates the dysfunction and degeneration of dopaminergic neurons in triple mutant mice. Our long-term goal is to develop a genetic mouse model that recapitulates all central features of PD and to characterize the molecular pathways responsible for PD pathogenesis.